Topoisomerase II

Antibiotic and Antimicrobial Drugs. The antimicrobial agents (119) flumequiae (160) and (161), and methylflumequiae (S-25930) (162) and (163) effectively eliminate a number of microbial pathogens via inhibition of the topoisomerase II enzyme of c-DNA containing bacteria (120) (see... 

Anthracyclins. Figure 2 Mechanisms of anthracycline-induced apoptosis of tumor cells. ROS, reactive oxygen species topo II, topoisomerase II cyt c, cytochrome c. 

Gyrase is another term for bacterial topoisomerase II. The enzyme consists of two A and two B subunits and is responsible for the negative supercoiling of the bacterial DNA. Negative supercoiling makes the bacterial DNA more compact and also more readily accessible to enzymes that cause duplication and transcription of the DNA to RNA. 

I topoisomerase of mammals is a 100 kD monomeric protein whose activity is ATP-independent. This enzyme binds to double-stranded DNA and cleaves one of the DNA strands of the duplex, simultaneously forming an enzyme-DNA covalent bond between a tyrosine residue and the 3 -phosphate of the cleaved DNA. The type II topoisomerases are dimeric enzymes, which are ATP-dependant. Two isoforms of topoisomerase II exist, topoisomerase a and (3, with apparent molecular weights of 170 and 180 kD. Topoisomerase... 

II cleaves the two complementary strands of DNA four base pairs apart and the resulting 5 -phosphoryl groups become covalently linked to a pair of tyrosine groups, one in each half of the dimeric topoisomerase II enzyme. Several groups of drugs are known that selectively inhibit topoisomerases in bacteria (quino-lones) or mammalian cells (etoposide, tenoposide). Quinolones are used to treat bacterial infections inhibitors of mammalian topoisomerases are cytostatic drugs used for the treatment of cancer. 

Topoisomerase II is a nuclear enzyme involved in replication, transcription. 

BOOS G, STOPPER H (2000) Genotoxicity of several clinically used topoisomerase II inhibitors. Toxicol Lett. 116 7-16. 

MARKOVITS J, LINASSIER C, FOSSE P, COUPRIE J, PIERRE J, JACQUEMIN-SABLON A, SAUCIER J M, LE PECQ J B, LARSEN A K (1989) Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res. 49 5111-17. 

YAMASHITA Y, KAWADA s, NAKANO H (1990) Induction of mammalian topoisomerase II dependent DNA cleavage by non-intercalative flavonoids genistein and oroboL Biochem Pharmacol. 39 737-44. 

The mechanism of action proposed is based on a direct binding to the channel and the following partial block of the ATP-binding pocket of CFTR (French et al., 1997), a mechanism similar to that used by genistein to inhibit the activity of other ATP-utilizing enzymes such as protein kinases and topoisomerase II (Polkowski and Mazurek, 2000 and refs therein). The selection of flavonoid compounds or the development of synthetic drugs reasonably selective for CFTR activation might be an area for future clinical trials. 

Identification of proteins that bind to Z-DNA added one further step to the establishment of the presence of Z-DNA in vivo and its possible biological role. Herbert and Rich [22] demonstrated an in vitro assay system where one type of double-stranded RNA adenosine deaminase, called DRAD-binding Z-DNA. There are evidences that topoisomerase II from Drosophila, hiunan and calf thymus recognizes a number of DNA shapes, including Z-DNA [34,35]. Bloomfield and coworkers [36] have found that the condensation of plasmids is enhanced by Z-DNA conformation in d(CG)n repeats. The information related to B-Z transition [31], the effect of ligands on it [28,29] and X-ray crystal structure data [37,38] appear to suggest that the possible biological role of this polymorphic form of DNA will be soon established. 

Nagase, M. Oto, J. Sugiyama, S. Yube, K. Takaishi, Y. Sakato, N. Apoptosis induction in HL-60 cells and inhibition of topoisomerase II by triterpene celastrol. Biosci. Biotechnol. Biochem. 2003, 67, 1883-1887. 

Topoisomerase is responsible for relieving the pressure on the DNA structure during unwinding by producing strand breaks. Topoisomerase I produces single-strand breaks, whereas topoisomerase II produces double-strand breaks. 

Etoposide causes multiple DNA double-strand breaks by inhibiting topoisomerase II. The pharmacokinetics of etoposide are described by a two-compartment model, with an a half-life of 0.5 to 1 hour and a (5 half-life of 3.4 to 8.3 hours. Approximately 30% of the dose is excreted unchanged by the kidney.16 Etoposide has shown activity in the treatment of several types of lymphoma, testicular and lung cancer, retinoblastoma, and carcinoma of unknown primary. The intravenous preparation has limited stability, so final concentrations should be 0.4 mg/mL. Intravenous administration needs to be slow to prevent hypotension. Oral bioavailability is approximately 50%, so oral dosages are approximate two times those of intravenous doses however, relatively low oral daily dosages are used for 1 to 2 weeks. Side effects include mucositis, myelosuppression, alopecia, phlebitis, hypersensitivity reactions, and secondary leukemias. 

Teniposide, a topoisomerase II inhibitor, is administered as an infusion over 30 to 60 minutes to prevent hypotension. The pharmacokinetics are described by a three-compartment model, with an a half-life of 0.75 hours, a (5 half-life of 4 hours, and a terminal half-life of 20 hours. Considerable variability in clearance of teniposide in children has been reported.17 Teniposide has shown activity in the treatment of acute lymphocytic leukemia, neuroblastoma, and non-Hodgkin s lymphoma. Side effects include myelosuppression, nausea, vomiting, mucositis, and venous irritation. Hypersensitivity reactions may be life-threatening. 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

Epirubicin inhibits both DNA and RNA polymerases and thus inhibits nucleic acid synthesis and topoisomerase II enzymes. Epirubicin pharmacokinetics are best described by a three-compartment model, with an a half-life of 4 to 5 minutes, a... 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

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